Imaging agents comprising barbituric acid derivatives

Abstract

The present invention relates to diagnostic imaging agents for in vivo imaging. The imaging agents comprise a synthetic barbituric acid derivative labelled at the 5-position with an imaging moiety suitable for diagnostic imaging in vivo. The invention also provides pharmaceutical and radiopharmaceutical compositions comprising the imaging agents, together with kits of the preparation of the radiopharmaceuticals. Also described are chelator conjugates of the barbituric acid derivative, which are suitable for the preparation of imaging agents comprising a radioactive or paramagnetic metal ion. The imaging agents are useful for the diagnostic imaging in vivo of various disease states, including atherosclerosis.

1 . An imaging agent which comprises a synthetic barbituric acid matrix metalloproteinase inhibitor labelled at the 5-position of the barbituric acid with an imaging moiety, wherein the imaging moiety can be detected following administration of said labelled synthetic barbituric acid matrix metalloproteinase inhibitor to the mammalian body in vivo, and said imaging moiety is chosen from: 
 (i) a radioactive metal ion;    (ii) a paramagnetic metal ion;    (iii) a gamma-emitting radioactive halogen;    (iv) a positron-emitting radioactive non-metal;    (v) a hyperpolarised NMR-active nucleus;    (vi) a reporter suitable for in vivo optical imaging;    (vii) a β-emitter suitable for intravascular detection.    
   
   
       2 . The imaging agent of  claim 1 , where the synthetic barbituric acid matrix metalloproteinase inhibitor ligand conjugate is of Formula I:  
       [{inhibitor}-(A) n ] m -[imaging moiety]  (I)  
     where: 
 {inhibitor} is the synthetic barbituric acid matrix metalloproteinase inhibitor;  
 -(A) n - is a linker group wherein each A is independently —CR 2 —, —CR═CR—, —C≡C—, —CR 2 CO 2 —, —CO 2 CR 2 —, —NRCO—, —CONR—, —NR(C═O)NR—, —NR(C═S)NR—, —SO 2 NR—, —NRSO 2 —, —CR 2 OCR 2 —, —CR 2 SCR 2 —, —CR 2 NRCR 2 —, a C 4-8  cycloheteroalkylene group, a C 4-8  cycloalkylene group, a C 5-12  arylene group, or a C 3-12  heteroarylene group, an amino acid or a monodisperse polyethyleneglycol (PEG) building block;  
 R is independently chosen from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxyalkyl or C 1-4  hydroxyalkyl;  
 n is an integer of value 0 to 10; and  
 m is 1, 2 or 3.  
 
   
   
       3 . The imaging agent of  claim 1 , where the synthetic barbituric acid matrix metalloproteinase inhibitor is conjugated to a ligand, and said ligand forms a metal complex with the radioactive metal ion or paramagnetic metal ion.  
   
   
       4 . The imaging agent of  claim 3 , where the ligand is a chelating agent.  
   
   
       5 . The imaging agent of  claim 3 , where the radioactive metal ion is a gamma emitter or a positron emitter.  
   
   
       6 . The imaging agent of  claim 5 , where the radioactive metal ion is  99m Tc,  111 In,  64 Cu,  67 Cu,  67 Ga or  68 Ga.  
   
   
       7 . The imaging agent of  claim 1  where the gamma-emitting radioactive halogen imaging moiety is  123 I.  
   
   
       8 . The imaging agent of  claim 1 , where the positron-emitting radioactive non-metal is chosen from  18 F,  11 C or  13 N.  
   
   
       9 . The imaging agent of  claim 1  where the synthetic  
     
       
         
         
             
             
         
       
       barbituric acid matrix metalloproteinase inhibitor is of Formula IV: 
 (IV)  
 where:  
 
       R 1  is R″ or a Z group;  
       R 2  is R″, Y or —NR 4 R 5 , where R 4  is H or an R″ group, R 5  is H, C 2-14  acyl, C 2-10  aminoalkyl or (N—C 2-14  acyl)C 2-10  aminoalkyl or an R″ group, or R 4  and R 5  together with the N atom to which they are attached form an optionally (N—C 2-14 )acylated C 2-8  cycloaminoalkylene ring;  
       R″ is independently C 1-14  alkyl, C 3-8  cycloalkyl, C 2-14  alkenyl, C 1-14  fluoroalkyl, C 1-14  perfluoroalkyl, C 6-14  aryl, C 2-14  heteroaryl or C 7-16  alkylaryl;  
       Z is a group of formula -A 1 O[A 2 O] p R 3  where p is 0 or 1, and A 1  and A 2  are independently C 1-10  alkylene, C 3-8  cycloalkylene, C 1-10  perfluoroalkylene, C 6-10  arylene or C 2-10  heteroarylene, and R 3  is an R group where R is independently chosen from H, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  alkoxyalkyl or C 1-4  hydroxyalkyl;  
       Y is a group of formula:  
       
         
           
           
               
               
           
         
       
       where E is CR 2 , O, S or NR 6 ; and R 6  is C 2-14  acyl, or an R″ or Z group.  
     
   
   
       10 . The imaging agent of  claim 9 , where R 2  is Y or —NR 4 R 5 .  
   
   
       11 . The imaging agent of  claim 9 , where the imaging moiety is attached to the R 2  substituent.  
   
   
       12 . The imaging agent of  claim 9 , of Formula V:  
     
       
         
         
             
             
         
       
       where E is CHR or NR 6  and R 1  is C 6-14  n-alkyl, or C 6-14  aryl.  
     
   
   
       13 . The imaging agent of  claim 12 , where E is NR 6  and R 6  is C 2-14  acyl; —(CH 2 ) d OH, where d is 2, 3, 4 or 5; or —C 6 H 4 X, where X is H, C 1-4  alkyl, Hal, OR, NR 2 , NO 2  or SO 2 NR 7 R 8 , where R 7  and R 8  are independently R groups, and R is as defined in  claim 9 .  
   
   
       14 . The imaging agent of  claim 12 , where R 1  is n-octyl, n-decyl, biphenyl, C 6 H 5 X or —C 6 H 4 —O—C 6 H 4 X where X is as defined in  claim 13 .  
   
   
       15 . A pharmaceutical composition which comprises the imaging agent of  claim 1  together with a biocompatible carrier, in a form suitable for mammalian administration.  
   
   
       16 . A radiopharmaceutical composition which comprises the imaging agent of  claim 1 , wherein the imaging moiety is radioactive, together with a biocompatible carrier, in a form suitable for mammalian administration.  
   
   
       17 . The radiopharmaceutical composition of  claim 16 , where the imaging moiety comprises a radioactive metal ion.  
   
   
       18 . The radiopharmaceutical composition of  claim 16 , where the imaging moiety comprises a positron-emitting radioactive non-metal or a gamma-emitting radioactive halogen.  
   
   
       19 . A conjugate of a synthetic barbituric acid matrix metlloproteinase inhibitor with a ligand, wherein the barbituric acid comprises a 5-position substituent, and said 5-position substituent comprises a ligand capable of forming a metal complex with a radioactive or paramagnetic metal ion which is resistant to transchelation.  
   
   
       20 . The conjugate of  claim 19 , of Formula Ib:  
       [{inhibitor}-(A) n ] m -[ligand]  (Ib),  where {inhibitor}, A, n and m are as defined in  claim 2 .    
   
   
       21 . The conjugate of  claim 19 , wherein the synthetic barbituric acid matrix metalloproteinase inhibitor is of Formula IV or Formula V of  claims 9  to  14 .  
   
   
       22 . The conjugate of  claim 19 , wherein the ligand is a chelating agent.  
   
   
       23 . The conjugate of  claim 22 , wherein the chelating agent has a diaminedioxime, N 2 S 2 , or N 3 S donor set.  
   
   
       24 . A kit for the preparation of the radiopharmaceutical composition of  claim 17 , which comprises: 
 a conjugate of a synthetic barbituric acid matrix metalloproteinase inhibitor with a ligand, wherein the barbituric acid comprises a 5-position substituent, and said 5position substituent comprises a ligand capable of forming a metal complex with a radioactive or paramagnetic metal ion which is resistant to transchelation, said conjugate being of Formula Ib:      [{inhibitor}-(A) n ] m -[ligand]  (Ib),    where {inhibitor} A, n and m are as defined in  claim 2;  and    wherein the ligand is a chelating agent.    
   
   
       25 . The kit of  claim 26 , where the radioactive metal ion is  99m Tc, and the kit further comprises a biocompatible reductant.  
   
   
       26 . A kit for the preparation of the radiopharmaceutical composition of  claim 18 , which comprises a precursor in sterile form which is a non-radioactive derivative of the barbituric acid matrix metalloproteinase inhibitor of claims  1 , wherein said non-radioactive derivative is capable of reaction with a source of the positron-emitting radioactive non-metal or gamma-emitting radioactive halogen to give the desired radiopharmaceutical.  
   
   
       27 . The kit of  claim 26 , where the source of the positron-emitting radioactive non-metal or gamma-emitting radioactive halogen is chosen from: 
 (i) halide ion;    (ii) F +  or I + ; or    (iii) an alkylating agent chosen from an alkyl or fluoroalkyl halide, tosylate, triflate or mesylate;    (iv) HS(CH 2 ) 3   18 F.    
   
   
       28 . The kit of  claim 26 , wherein the non-radioactive derivative is chosen from: 
 (i) an organometallic derivative such as a trialkylstannane or a trialkylsilane;    (ii) a derivative containing an alkyl or aryl iodide or bromide, alkyl tosylate or alkyl mesylate for nucleophilic substitution;    (iii) a derivative containing an aromatic ring activated towards nucleophilic or electrophilic substitution;    (iv) a derivative containing a functional group which undergoes facile alkylation;    (v) a derivative which undergoes alkylation with an alkyl thiol to give a thioether.    
   
   
       29 . The kit of  claim 26 , where the precursor is bound to a solid phase.  
   
   
       30 . Use of the imaging agent of  claim 1  for the diagnostic imaging of atherosclerosis.  
   
   
       31 . Use of the imaging agent of  claim 1  for the diagnostic imaging of unstable plaques.  
   
   
       32 . Use of the imaging agent of  claim 1  for the intravascular detection of atherosclerosis.